A prodrug, also referred to as a precursor of a drug, refers to a compound which achieves pharmacological action after the conversion in an organism. A prodrug per se has no or little bioactivity, and releases an active agent after metabolism in vivo. The purpose of investigating and preparing a prodrug is to increase the bioavailability, modify the solubility, enhance the targeting properties, or reduce the toxicity or side effects of the parent drug. It is advantageous for many drugs, especially those having low bioavailability, poor water solubility or high toxic side effects, to be prepared into prodrugs.
In general, it is required in clinic that a prodrug can be quickly dissociated into a ligand and a parent drug after entering the body, and the ligand is non-toxic. The parent drug thus released can exert pharmaceutical effects, and the non-toxic ligand is of no harm to the body.
However, it is very difficult to achieve such a purpose. For example, fospropofol disodium marketed in the US in 2008 is a prodrug of propofol, which has the following metabolism in vivo:

Although fospropofol addresses the problem of poor water solubility of propofol, it can be seen from the above scheme that the metabolism of fospropofol in vivo would result in production of formaldehyde having high toxicity, which would cause unnecessary harm to patients. In addition, according to the published data (as shown below), fospropofol is significantly higher in dosage and is much longer in latent period and persistent period, in comparison to propofol.
Name ofDosageLatentPersistentDrug(mg/kg)Period (s)period (s)Data SourcesPropofol1510.7No ReportBr. J. Anaesth. (1980), 52, 731(1.25 * ED50)(mice)258.4 ± 1.1324.8 ± 98.9mice, results from the present lab(2 * ED50)Fospropofol85105No ReportFDA Application NO. (NDA)(1.25 * ED50)022244136 81804Pharmacology Reviews of(2 * ED50)Fosproporfol (Part I) page 30-31(mice)
This suggests that fospropofol is difficult to dissociate quickly in vivo, and thus is not an ideal prodrug of propofol. A suitable ligand is critical for an ideal prodrug. As such, it is one of the urgent tasks for a skilled artisan in the field of pharmacy to search for good ligands for prodrugs. A “good ligand” should satisfy the following criteria: the prodrug formed from the ligand and a parent drug has improved physicochemical properties or bioavailability, and can quickly release the parent drug after entering the body, and the ligand has no or little toxicity.